Document

Report
MEDICATION ASSISTED
TREATMENT
Michael Fingerhood MD FACP
Medications
• Opiates
• Naltrexone
• Methadone
• Buprenorphine
• Nicotine
• Buproprion
• Varenicline
• Alcohol
• Naltrexone
• Acamprosate
• Disulfiram
• Cocaine
• ????
DEFINING the DISEASE:
Opioid Dependence (DSM IV)
1.
2.
3.
4.
Tolerance
Withdrawal
Larger amounts/longer period than intended
Inability to/persistent desire to cut down or
control
5. Increased amount of time spent in activities
necessary to obtain
6. Social, occupational and recreational activities
given up or reduced
7. Opioid use is continued despite adverse
consequences
THREE OR MORE IN THE PAST YEAR
DEFINING:
Opioid Dependence?
1.
2.
3.
4.
Tolerance
Withdrawal
Larger amounts/longer period than intended
Inability to/persistent desire to cut down or
control
5. Increased amount of time spent in activities
necessary to obtain
6. Social, occupational and recreational activities
given up or reduced
7. Opioid use is continued despite adverse
consequences
Opium History
• First cultivation of opium poppies was in
Mesopotamia, approximately 3400 B.C., plant
called Hul Gil, the "joy plant”
• The Greek gods Hypnos (Sleep), Nyx (Night),
and Thanatos (Death) were depicted wreathed
in poppies
• The Persian physician, al-Razi (845-930 A.D.)
made use of opium in anesthesia and
recommended its use for the treatment of
melancholy.
Opium History
• Between 400 and 1200 AD, Arab traders
introduced opium to China.
• 14th century Ottoman Empire-opium used to
treat headache and back pain.
• 15th century China- first officially recorded use
of opium as a recreational drug.
• 1874- heroin developed
• 1898-heroin marketed by Bayer as safe
pediatric cough suppressant
Opiates & Opioids
Opiates = naturally present in
opium
• e.g. morphine, codeine, thebaine
Opioids = manufactured
• Semisynthetics are derived from an
opiate
• heroin from morphine
• buprenorphine from thebaine
• Synthetics are completely man-made
to work like opiates
• methadone
Narcotic Regulation in US
• 1914- Harrison Narcotics Tax Act
• 1925- Linder vs United States
• 1964- Methadone introduced as experimental
treatment for opioid addiction
• 1968- Bureau of Narcotic and Dangerous Drugs
formed (changed to DEA in 1973)
Rationale for
Opioid Replacement Therapy
• Traditional treatment has been to provide
opioid agonist therapy
• Methadone (Dolophine®)
• Levo-Alpha Acetyl Methadol (LAAM) – not available
• Stabilize neuronal circuitry
• Mu occupation/blockade
• Cross-tolerant, long-acting, oral
•
•
•
•
Prevent withdrawal and craving
Extinguish compulsive behavior
Prevent spread of HIV and HCV
Prevent criminal activity
Traditional 12 Step Drug Treatment
1. Accepting powerlessness
2. Disease identification
3. Surrender to a Higher Power
4. Commitment to AA/NA
5. Commitment to abstinence
6. Sober social support
7. Intention to avoid high-risk situations
Effective Treatment of Opiate Addiction
NIH Consensus Development Conference
November 17-19, 1997
 Opiate dependence is a brain-related medical disorder
 Treatment is effective “Although a drug-free state represents an optimal treatment
goal, research has demonstrated that this goal cannot be
achieved or sustained by the majority of opiate-dependent
people.”
 Reduce unnecessary regulation of long-acting agonist
treatment programs
 Improve training of health care professionals in
treatment of opiate dependence
THE PROBLEM:
Emergency room mentions of opioid use
95,000
90,000
80,000
70,000
60,000
50,000
40,000
30,000
88 89 90 91 92 93 94 95 96 97 98
99 00 01
DAWN, 2002
Trends In Emergency Department
Mentions of Opioids:1991-2001
Other Opioid Analgesics
Heroin/Morphine
120,000
100,000
80,000
60,000
40,000
20,000
0
1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002
DAWN, 2003
Changing Route of Heroin Administration
Injection
Inhalation
Smoking
Oral
Other
100%
80%
60%
40%
20%
0%
1992 1993 1994 1995 1996 1997 1998 1999 2000
Treatment Episode Data System, 1992-2000
New Non-Medical Use of Opioid
Medications
Thousands of New Users
3,000
2,500
All Ages
2,000
1,500
Aged 18
or Older
1,000
Aged
Under
18
500
0
1965
1970
1975 1980 1985
1990 1995
2000
NSDUH, SAMHSA, 2003
Non-Medical Use of Opioid Medications
• Non-medical use of any prescription
psychotherapeutic drug was second only to
past-year use of marijuana (11.3 million vs.
25.5 million)
• Ages 18-25 had highest rates for all pain
relievers, followed by 12 to 17 year olds
• Males had higher rates except for youths 1217, where females had higher rates
• Most non-medical users of psychotherapeutic
drugs also used other illicit drugs (82%)
NSDUH, 2004
OPIOID Treatment Admissions per 100,000
1994
Incomplete data
<5
5-9
10-13
Source: SAMHSA
14-24
25+
OPIOID Treatment Admissions per 100,000
2000
Incomplete data
<5
5-9
10-13
Source: SAMHSA
14-24
25+
OPIOID Treatment Admissions per 100,000
2005
Incomplete data
<5
5-9
10-13
Source: SAMHSA
14-24
25+
Opioid dependence is costly
• Medical Costs
• Mental illness
• An environmental and disease stressor
• Co-morbid interactions
•
•
•
•
Trauma and infections
Hepatitis and HIV
$20 billion per year total costs
$1.2 billion per year health care costs
• Non-medical costs- work, legal, prison
Problems With System Prior to 2000
• Less than 20% of opioid dependent
persons are receiving treatment in traditional
settings
• Poor clinic retention
• Environment inhibits recovery
• Highly regulated doses & take homes
• Criteria exclude persons under age 18
• Infrastructure of care
• High turnover of staff
• Ability to get to treatment may be limited
What the opioid dependent patient
feels…
Dole, Arch Int Med, 1966
The Opioid Disease Process
• Repeated exposure to short acting opioids
leads to neuronal adaptations
• Meso-limbic dopaminergic system
• adaptations in G protein-coupled receptors
• up regulation of cyclic cAMP second messenger pathway
• These changes:
• Mediate tolerance, withdrawal, craving,
administration
• Basis of specific pharmacotherapies to stabilize
neuronal circuits
Rationale for
Opioid Replacement Therapy
• Traditional treatment has been to provide
opioid agonist therapy
• Methadone (Dolophine®)
• Levo-Alpha Acetyl Methadol (LAAM) – not available
• Stabilize neuronal circuitry
• Mu occupation/blockade
• Cross-tolerant, long-acting, oral
•
•
•
•
Prevent withdrawal and craving
Extinguish compulsive behavior
Prevent spread of HIV and HCV
Prevent criminal activity
Problems With System 1999
• Less than 20% of opioid dependent
persons are receiving treatment in traditional
settings
• Poor clinic retention
• Environment inhibits recovery
• Highly regulated doses & take homes
• Criteria exclude persons under age 18
• Infrastructure of care
• High turnover of staff
• Ability to get to treatment may be limited
Drug Abuse Treatment Act (DATA) of
2000
•
Allowed “Qualified” physicians to treat opioid
dependence outside methadone facilities
1. Addiction certification from approved organization, or
2. Physician in clinical trial of qualifying medication, or
3. Complete 8-hour course from approved organization
•
•
DEA issues (free) to qualifying physicians a new
DEA number to use medication for opioid
dependence
As of today, only one medication formulation is
approved for this use
Opioid Treatment: Changing Approach
Methadone Clinic
Buprenorphine
• Criteria:
Withdrawal
12 months use
• Criteria:
DSM IV
No time criteria
• Dose regulated
• MD sets dose
• Age > 18
• Age > 16
• Limited take homes
• Take homes (30 days)
• Services “required”
• Services must be “available”
Treatment vs. Addiction
Methadone
Buprenorphine
Heroin
Oral or SL
IV, IN
30 minutes
Immediate
24-36 hours
3-6 hours
Absent
Marked
Route
Onset
Duration
Euphoria
Stabilization by Blockade Treatment
Methadone Effectiveness
Gunne & Gronbladh, 1984
Baseline
Methadone
H H H H
Regular Outpatient
H H H H
H H H H
H H H H
H H H H
H H H H
H H H H
H H H H
H
H
Methadone Effectiveness
Gunne & Gronbladh, 1984
After 2 Years
Methadone
No Methadone
P P H1
2
3
H H H H
H H H H
P H H H
H H H
H
1- Sepsis & endocarditis
2- Leg amputation
3- Sepsis
Methadone Effectiveness
Gunne & Gronbladh, 1984
After 5 Years
Methadone
P H H
No Methadone
P P
P
H
Methadone Treatment Decreases
HIV Seroincidence
Metzger et al. JAIDS 1993;6:1049.
Methadone
Out-of-treatment
45
40
% seropositive
35
30
25
20
15
10
5
0
Baseline
1 yr.
2 yr.
3 yr.
Buprenorphine, Methadone, LAAM:
Treatment Retention
Percent Retained
100
80
73% Hi Meth
60
58% Bup
40
53% LAAM
20
20% Lo Meth
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
Study Week
Johnson RE, et al (2000)
Discrepancy Between Population Abusing
Opioids and Population Treated
(courtesyCSAT/SAMHSA)
Opioid Abuse
Methadone
Treatment
Treatment Under
the Waiver (BUP)
NSDUH Past Month
Use 2002
TEDS 2002 Admissions Involving
Methadone Treatment
Patient Study BUP
Evaluation 2005
96% Non-heroin
Only
4,549,570 reported opioid abuse
Heroin Only
40% Nonheroin
Only
83% Heroin
Only
111,885 admissions involved
methadone treatment
434 patients recruited
from 132 sites
Non-heroin Opioids Only
Both
Buprenorphine’s Properties
•
•
•
•
•
•
Modest  agonist activity with ceiling
Long half life
Precipitated withdrawal if taken after full
agonist
Decreased risk of respiratory, CNS depression
Sublingual route of administration
“Combo” tablet with naloxone limits abuse by
injection
Buprenorphine Safety
• No alteration of cognitive functioning
• feel “normal”
• No organ damage
• Early concern of hepatic toxicity unconfirmed
• No evidence of QT prolongation
• Ceiling prevents respiratory depression, OD
(Overdose reports with combining use with
benzodiazepines)
• No clinically significant interactions with other
drugs
Appropriateness for Office-based Treatment
• Patient is less likely to be an appropriate
candidate for office-based treatment:
• Dependence on high doses of benzodiazepines,
alcohol, or other CNS depressants
• Significant psychiatric co-morbidity
• Multiple previous treatments (methadone) and
relapses
Most often heard quotes with
Buprenorphine
“Doc, I feel normal”
“I wake up not sick”
“I have my life back”
• Treatment in normal medical settings:
• Encourages continuity of medical/specialty care
• Encourages relationship building with clinicians
• Legitimize opioid dependence as a normal, treatable,
chronic illness
Remaining in treatment (nr)
Buprenorphine: Retention and Mortality
0 deaths
20
15
10
4 deaths
Bup 6 day detox
Bup Maintenance
5
0
0
50
100
150
200
250
Treatment duration (days)
300
350
All Patients received group CBT
Relapse Prevention, Weekly
Individual Counseling, 3x Weekly
Urine Screens. n=20 per group
Kakko J, Lancet 2003
Who were the first patients?
Percent of Patients Treated
Addiction Physician Survey 2003
60%
50%
40%
30%
20%
10%
0%
New to Substance
Abuse Treatm ent
New to Medication- Transitioned from
Assisted Treatm ent
Methadone
Addicted to NonHeroin Opioids*
Opioid Dependence Treatment
in Primary Care
At 24 weeks, 59% remained
in treatment
Stein, JGIM 2005
Buprenorphine:
Reduces Other Drug Use
Fudala, NEJM 2003
Buprenorphine Diversion
OXYCODONE
METHADONE
BUPRENORPHINE
Cicero, NEJM 2005
Patient 1
• LS is a 48F, hospital communications
supervisor, started snorting heroin at age
17. On methadone several times- did not
like “crowd at methadone program.”
Single mom, raised son, who just
graduated college. She uses heroin 3x
day “to not be sick”; failed detox many
times. Already my patient for HTN and
family issues related to Huntington’s
disease
Patient 2
• SB is a 34M with Type I DM, HTN and
retinopathy, recently moved to Baltimore.
Works as concierge at downtown hotel.
Using heroin since age 21- snort and IV.
Active in NA, but keeps relapsing. Was on
methadone- made too drowsy. Heard
about buprenorphine and interested in
finding out more.
Our Buprenorphine Outcomes at One
Year
• All patients initiated on buprenorphine
August 2003 through September 2007
• Visits 15 minutes; frequency at discretion of
provider; non-witnessed urines checked for
temperature
Outcomes Comprehensive Care Practice
•
Co-morbidities- Heptatitis C-49%;
psychiatric disorders 49%; HIV 14%;
chronic pain 18%
Outcomes•
At the end of one year- 145 patients
(57%) were still receiving buprenorphine
treatment
• Overall 65% of month-long treatment
blocks were opioid negative
Outcomes Comprehensive Care Practice
•
Co-morbidities- Heptatitis C-49%;
psychiatric disorders 49%; HIV 14%;
chronic pain 18%
Outcomes•
At the end of one year- 145 patients
(57%) were still receiving buprenorphine
treatment
• Overall 65% of month-long treatment
blocks were opioid negative
Buprenorphine Outcomes
Comprehensive Care Practice
• Treatment success higher for non-heroin
users; all other demographic variables not
significantly different
• Non-retained patients (109)- 63 lost to f/u;
10 lost insurance; 21 discontinued; 8
transferred to methadone maintenance; 2
had adverse effect; 5 deaths – 3 overdose
(none on buprenorphine at time of death);
1 AIDS; 1 cerebral hemorrhage.
Combined pharmacotherapies…
• Randomized controlled trial- 11 centers
• N=1383 divided in 9 arms- CBI & no pills,
MM/CBI and naltrexone, MM/CBI and
acamprosate, MM/CBI and placebo,
MM/CBI and both acamprosate and
naltrexone, MM amd acamprosate, MM and
naltrexone, MM and placebo, MM and both
acamprosate and naltrexone.
• Medical Management- provider provided
support during 9 visits, focusing on
support of abstinence (e.g. go to AA) and
medication adherence
• Cognitive Behavioral Interventionintensive counseling delivered by outside
addiction specialist
• Patients enrolled after 4-21 days of
abstinence
• Met DSM criteria and quantity >14/week in
women, >21/week in men and >2 heavy
drinking days in 30 day period
• Exclusion-other substance abuse
(nicotine and cannabis okay), on psych
meds, unstable medical condition
• Study population- 428 women and 955
men, mean age 44, 71% had at least 12
years of education, 42% were married.
• Prior to randomization, 2.3% were
medically detoxified.
• Across treatment groups, no significant
differences in baseline measures; % days
abstinent ranged from 23.5-29.8%.
Adverse events
•
•
•
•
Acamprosate- nausea 24%, diarrhea 65%*
Naltrexone- nausea 34%*, diarrhea 31%
Both- nausea 42%*, diarrhea 56%*
Placebo- nausea 21%, diarrhea 35%
Results
• Mean % days abstinent• Only significant change was in no CBI/
naltrexone v. placebo- 80.6 v 75.1 p=.009
• In no comparison was acamprosate better
than placebo.
• CBI/naltrexone was no better than placebo
Injectable, sustained release
naltrexone…
• Randomized, double-blind, placebo
controlled 6 month trial of 624 subjects.
• 3 treatment groups- placebo, depot
naltrexone 190 mg or 380 mg.
Median Heavy Drinking Days per Month for Each Treatment Group Overall and by Sex
Garbutt, J. C. et al. JAMA 2005;293:1617-1625.
Copyright restrictions may
apply.
Author conclusions
• “Long acting naltrexone was well tolerated
and resulted in reductions in heavy
drinking”
• “These data indicate that long acting
naltrexone can be of benefit in the
treatment of opoid dependence”
Study 1
• Multi-center randomized double blind
placebo controlled study of 1210 smokers
who received 12 weeks of either placebo
or varenciline 1mg 2x/day
• Outcome measures- abstinence for weeks
13-24 and weeks 13-52. (Subjects on
varenicline who were abstinent for at least
7 days at week 12 were re-randomized to
receive placebo or varenicline for another
12 weeks)
Study 1 Results
placebo
Abstinence 49.6%
for weeks
13-24
Abstinence 36.9%
for weeks
13-52 (if
successful
for >7 days
before week
13)
varenicline
70.5%
p<.001
43.6%
p=.02
Study 2
• Double-blind placebo controlled multicenter study of 12 weeks of treatment with
placebo, buproprion 150 2x/day and
vareniciline 1mg 2x/day in 1025 smokers
• Participants could have no more than 3
months abstinence in past year and could
not have ever received buproprion before
• Outcome measures- abstinence rates for
weeks 9-12 and abstinence at 52 weeks
Study 2- Results
buproprion
varencline
Abstinence 17.7%
weeks 8-12
29.5%
44.0%
Abstinence 8.4%
weeks 9-52
16.1%
(p=.057)
21.9%
(p<.001)
Placebo

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